Uveal melanoma is a rare malignancy of the eye. Survival rates are poor. Metastatic disease occurs frequently and invariably results in death. At present there is insufficient evidence to support the use of any systemic therapy regimen to treat uveal melanoma. Micrometastases, microscopic deposits of tumor that have spread via the bloodstream, are present in many patients with uveal melanoma at diagnosis. Thus, an effective strategy to improve survival would be to suppress the growth of these deposits, rather than prevent their development or treat when they become clinically evident and refractory to treatment. The overall objective is to translate recent advances in the understanding of the molecular mechanisms of the progression of micrometastases in uveal melanoma to the treatment of patients. Interrelated clinical studies with laboratory correlates are proposed. Specific tumor genotypes have been identified that are strongly associated with the presence of micrometastases in patients with uveal melanoma. The use of fine needle aspiration biopsy and fluorescence in situ hybridization to detect these genotypes in patients with primary uveal melanoma will be evaluated. Gene expression profiling of tumor from patients with uveal melanoma who develop metastasis has identified alterations in specific factors involved in the escape of tumor cells from immune surveillance and their invasion into tissues. The relationship between tumor genotype and the expression of these factors will be assessed. In patients with tumors characterized by the high-risk genotypes, a clinical trial will be performed to examine the effects on disease-free survival of a systemic therapy regimen designed to activate antitumor immune cells and inhibit tumor cell invasion after local therapy. The relationship between the expression of the molecular regulators of immune escape and invasion and the clinical outcome will also be assessed in this trial. This project will establish a clinical framework to develop effective treatments for patients with uveal melanoma. It may lead to an effective systemic therapy regimen. In addition, the studies of tumor genotype and factors involved in immune escape and invasion may prove useful in identifying prognostic/predictive biomarkers as well as suggest new therapeutic approaches. PUBLIC HEALTH RELEVANCE: Patients with uveal melanoma, a malignancy that starts in the eye, have a poor prognosis. Chemotherapy is not effective. Micrometastases, microscopic deposits of tumor that have spread via the bloodstream, are present in many patients with uveal melanoma at diagnosis. This project will test new methods of identifying and inhibiting these deposits.